Fabry disease

Fabry disease resulting from a deficiency of α-galactosidase A leads to the accumulation of globotriaosylceramide in various organs. Because the disease is an X-linked recessive disorder, males tend to develop more symptoms and more severe symptoms than females. There are also some variants of Fabry disease, and cardiac variant (cardiac Fabry disease) has the dysfunctions only in heart. Cardiac manifestations in Fabry disease are initially symmetrical and concentric left ventricular hypertrophy, and later progressive cardiac dysfunction with localized thinning of the basal posterior wall. In recent years, enzyme replacement therapy has been performed as a treatment for Fabry disease, and the initiation of this therapy is expected before the cardiac fibrosis develops. Therefore, early diagnosis of Fabry disease is essential, and echocardiography is an indispensable tool for clinical practice of this disease. Then, it is necessary to remember this disease as a differential diagnosis when encountering unexplained left ventricular hypertrophy.     

Fabry disease

Fabry disease (FD) is an X-linked lysosomal disorder caused by the deficient activity of the enzyme alpha-galactosidase A, which leads to multisystemic storage of globotriaosylceramide in visceral tissues and vascular endothelium. FD manifests primarily in affected hemizygous men, with a wide range of clinical signs in heterozygous women. Acroparesthesias, angiokeratomas, pain crisis, and cornea verticillata are early manifestations of FD. With age, severe complications involving the kidneys, heart, and brain cause considerable morbidity and premature death. Although the clinical onset of FD occurs in childhood, diagnosis is often delayed or missed. In men, the diagnosis must be confirmed biochemically by demonstration of decreased levels of alpha-galactosidase A activity. In women, the disease is diagnosed by identification of a mutation in the alpha-galactosidase A gene. Until a few years ago, the existing treatment for FD was based on clinical manifestations, but the advent of enzyme replacement therapy should stimulate the identification of the signs and symptoms suggestive of this disorder to allow earlier diagnosis and treatment.     

Anemia is a new complication in Fabry disease: data from the Fabry Outcome Survey

BACKGROUND: The prevalence and causes of anemia among patients with Fabry disease are unknown. METHODS: In a cross-sectional study we examined hemoglobin concentrations of patients with Fabry disease using a large international database, the Fabry Outcome Survey (FOS), and analyzed the association of renal function, heart failure, gastrointestinal symptoms, and inflammation, with anemia (hemoglobin <12 g/dL in females and <13 g/dL in males). RESULTS: Anemia was present in 34% of 345 patients with Fabry disease. Median hemoglobin in 158 females was 12.9 g/dL and the median hemoglobin of 187 male patients was 13.2 g/dL. The prevalence of anemia among females was 20%, and among males 47%. Among patients with normal renal function [estimated glomerular filtration rate (GFR) >90 mL/min/1.73 m(2)] and anemia, heart failure [New York Heart Association (NYHA) class II to IV] and/or elevated C-reactive protein (CRP) levels were documented in 82% of patients. Up to 67% of patients with decreased estimated GFR presented with anemia. There was also a trend for lower hemoglobin levels among patients with signs of inflammation (defined by an elevated CRP level). We observed no association of the presence of gastrointestinal symptoms with anemia. Analyses in 53 patients receiving enzyme replacement therapy for up to 2 years, suggest no effect on anemia. CONCLUSION: The results of this study point to a high prevalence of anemia among patients with Fabry disease that is in most instances related to impaired renal function, heart failure, and inflammation. This finding may be of clinical relevance, because anemia is a major risk factor for patients with kidney disease, heart failure, or stroke, which are important manifestations of Fabry disease.     

Fabry disease: diagnosis and treatment

Fabry disease is an X-linked lysosomal storage disorder that results from a deficiency of the enzyme alpha-galactosidase A (alpha-Gal A). The lack of alpha-Gal A causes an intracellular accumulation of glycosphingolipids, mainly globotriaosyceramide (GL3). Affected organs include, among others, the vascular endothelium, heart, brain, and kidneys, leading to end-stage renal disease (ESRD). Since Fabry disease cannot be cured at present, clinical management is symptomatic. Enzyme replacement therapy (ERT) with recombinant alpha-Gal A has been introduced as a new therapeutic option for the treatment of Fabry patients. Short-term (one year) clinical studies have positively correlated ERT with improvement of clinical symptoms and microvascular endothelial cell clearance. Treatment outcome concerning severe organ manifestations such as proteinuria and renal function impairment, left ventricular hypertrophy, and heart failure in the long run has yet to be shown. In our studies we used sensitive and noninvasive techniques such as ultrasound-based strain rate imaging and magnetic resonance imaging (MRI), combined with MR-spectroscopy (MR-S), for the quantification of functional abnormalities at an early stage of the disease and during long-term follow-up. Future issues should determine the appropriate timing to start therapy and how children and heterozygous females should be managed. Given the diagnostic and therapeutic potential today, it is of importance to identify patients at an early stage and to start therapeutic intervention before progression of organ damage is inevitable.     

Prevalence of Fabry disease in dialysis patients: Japan Fabry disease screening study (J-FAST)

Background

In Fabry disease, progressive glycolipid accumulation leads to damage in kidney and other organs. This study was designed to determine the prevalence rate of Fabry disease in Japanese dialysis patients.

Methods

All dialysis patients agreeing to Japan Fabry disease screening study (J-FAST) with informed consent were selected except for Fabry disease. The screening was performed by a method of measuring plasma and/or leukocytes lysosomal α-galactosidase A protein level and α-galactosidase A activity. If positive, genetic analysis was carried out upon patient’s agreement.

Results

J-FAST dealt with 8547 patients (male 5408, female 3139). At the tertiary examination, 26 out of 8547 patients were found to be positive. Six out of 26 patients could not accept genetic analysis because of death. Remaining 20 patients agreed with genetic analysis; then 2 patients (male 2, female 0) had a variation of the α-Gal gene and 11 patients showed E66Q variations. Therefore, the frequency of Fabry disease in J-FAST was 0.04 % (2/5408) in males and 0 % (0/3139) in females, and then 0.02 % (2/8547) in all patients. The presumptive clinical diagnoses of end-stage kidney disease (ESKD) were 10 chronic glomerulonephritis, 7 diabetic nephropathy, 3 unknown etiology, 3 nephrosclerosis, 1 gouty nephropathy, 1 autosomal dominant polycystic kidney disease and 1 renal tuberculosis among 26 tertiary positive patients. Two male Fabry patients were initially diagnosed as nephrosclerosis and chronic glomerulonephritis.

Conclusions

The prevalence rate of Fabry disease in J-FAST was 0.02 %. Moreover, Fabry disease could not be ruled out as the clinical diagnosis of ESKD.

     

Fabry disease: renal biopsy-proven cases from China

BACKGROUND: Fabry disease is a rare metabolic disorder resulting from deficient activity of the lysosomal enzyme alpha-galactosidase A (alpha-GalA). Renal involvement is the major cause of morbidity and mortality in male patients. Here, we describe the largest series ever reported for this condition in China. METHODS: Nine patients were enrolled in this study. Routine light microscopy (including toluidine blue staining), immunofluorescence and electron microscopic examinations were performed. We measured alpha-GalA activity in leukocyte and gene mutation analysis. Clinical and laboratory data of the patients were collected. RESULTS: Eight of the 9 patients were hemizygous males. Proteinuria was obvious in all patients. Three patients presented with mild renal function impairment. Light microscopy revealed glomeruli full of enlarged podocytes with abundant foamy cytoplasm. Toluidine blue stain revealed abundant cytoplasmic granular inclusions within the podocytes, tubular epithelial cells and endothelial cells of peritubular capillaries. Electron microscopy showed abundant electron-dense myelin figures within the podocyte cytoplasm. Arteriolar hyalinization and occlusion were also observed. Extrarenal manifestations, including acroparesthesia, hypohidrosis, abnormal electrocardiography and angiokeratoma were noted. No cornea verticillata or lenticular opacities were observed. These patients had about 0.3%-1.3% residual alpha-GalA activity in leukocytes. We identified a novel missense mutation (F273L) causing nonclassical Fabry disease.CONCLUSIONS: Fabry disease is relatively rare in China. Renal biopsy and specific staining is efficacious in the correct diagnosis of the disease. Discrepancies in the clinical manifestations of Fabry disease (i.e., eye disorders and hypertension) exist between cases found in China and those detailed in Western reports.     

Fabry病一例

Fabry病是X性连锁隐性遗传的α半乳糖苷酶A缺乏遗传性疾病.该病十分罕见,迄今国内仅见10余例报道.现报告1例.男性,28岁,20余年前出现双手指、足趾末端烧灼样疼痛,渐累及双手、足小关节及周围肌肉,疼痛时行走困难.上述症状多于感冒、高温天气、发热后发作且逐渐加重,持续时间不等,体温下降后可缓解,未治疗.10年前疼痛累及双腕、肩、膝及左踝等大关节,伴纳差、心悸、胸痛,当地医院诊断为类风湿关节炎,治疗无效.3年前出现双下肢水肿,伴双臂点状红斑,界限清楚,不突出皮肤,当地医院查尿常规蛋白±～+.为进一步治疗于2010年6月29日入我院.     

Current management of Fabry disease

Fabry disease is a rare X-linked lysosomal storage disease leading to systemic involvement, mainly through GL-3 endothelial deposition. Initial symptoms may occur during childhood (acroparesthesia, angiokeratoma), prior to adulthood complications, i.e. renal, ocular, cerebral, neurological and cardiovascular involvement. An early diagnosis of the disease may be challenging because of a frequent atypical clinical presentation. Indeed, independent of conservative treatment (pain, proteinuria, chronic renal failure, arterial hypertension, heart failure, etc), enzyme therapy using recombinant alpha-galactosidase (agalsidase) has provided a safe pathophysiological approach, leading to significant organ functional improvement (mainly kidney and heart) and improved quality of life, which parallels tissue GL-3 clearance. Such a treatment is safe and efficient but its biweekly intravenous administration is still uncomfortable, so that further alternative therapeutic approaches may be encouraged.     

Parapelvic kidney cysts: a distinguishing feature with high prevalence in Fabry disease

BACKGROUND: Fabry disease is an X-linked generalized progressive debilitating lysosomal storage disorder. The disease usually manifests in childhood, but the diagnosis is often made following the occurrence of late-stage complications such as progressive kidney failure. In order to identify key novel renal diagnostic imaging features of Fabry disease, we conducted a cross sectional case-control study of kidney involvement in patients with Fabry disease. METHODS: Twenty-four patients (mean age 36.1 +/- 8.1 years, median 37 years, range 20 to 48 years) with chronic neuropathic pain who were enrolled in an enzyme replacement trial underwent prospective renal imaging evaluation with magnetic resonance imaging (MRI) and computed tomography (CT) at the National Institutes of Health, Bethesda, Maryland. We concurrently enrolled 19 age-matched healthy controls (mean age 34.6 +/- 12.0 years, median 33 years, range 18 to 61 years). The presence and localization of kidney cysts as well as the ratio of the signal intensity between medulla and cortex were determined. RESULTS: Fifty percent of the Fabry disease patients had renal sinus cysts, compared to one individual (7%) in the control group. The ratio of the signal intensity between medulla and cortex on T2-weighted scans in Fabry disease patients with sinus cysts was elevated compared with Fabry disease patients without cysts (P= 0.0083), and elevated in Fabry disease patients without cysts compared with normal controls without cysts (P= 0.0173). CONCLUSION: The finding of multiple renal sinus cysts in the workup of a patient with kidney disease patient should strongly suggest the consideration of Fabry disease in the differential diagnosis. The cause of such cysts in Fabry disease remains to be elaborated.     

Fabry disease in the era of enzyme replacement therapy: a renal perspective

Fabry disease, the second most prevalent lysosomal storage disorder after Gaucher disease, is caused by mutations of the gene encoding the lysosomal hydrolase, -galactosidase A. The enzymatic defect is inherited in an X-linked recessive fashion and leads to systemic glycosphingolipid deposition, resulting in profound dysfunction of neurological, renal, cardiac, and cerebrovascular systems. Although symptoms typically appear in childhood in hemizygous males and some heterozygous females, the diagnosis is often delayed or unrecognized, owing to variable presentations and low incidence. The initial phase begins in childhood or adolescence and is characterized by neuropathic pain, angiokeratomas, and ocular deposits. The later phase is distinguished by progressive cardiac, cerebral, and renal involvement, leading to multi-organ dysfunction and death. Recently published clinical trials have demonstrated the efficacy of enzyme replacement therapy in decreasing neuropathic pain and substrate deposition in target organs. Pediatricians have a key role to play in making the diagnosis, so that therapy can be initiated before irreversible tissue injury develops. Further research is required to determine optimal dosing protocols for treatment and to establish whether therapy can retard the progression of organ dysfunction, or even prevent these complications altogether.